Off Label Changes Coming - Coalition for Healthcare Communication

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October 2011, Vol. 4, No. 10

Label Changes Coming?

Ruling Prompts
New Legal Challenges

Pharmaceutical companies are unleashing fresh legal challenges to FDA’s
restrictions on off
label promotion, arguing that they contain the same

and content
based restrictions that were struck down by the
Supreme Court in the Vermont data mining ca
Sorrell vs. IMS Health.
courts appear willing to listen. Is an end to off
label prosecutions on the

By Kate Rawson

In the sometimes hazy world of pharmaceutical marketing, industry has yearned for one thing:
definitive rules from the Food
& Drug Administration on off
label promotion.

Marketers have long complained about a lack of clarity from FDA on how to discuss unapproved
uses of prescription drugs and biologics without running afoul of the Department of Justice. A
statutory “safe harbo
r” for the dissemination of journal articles expired five years ago, and
companies say current FDA guidance doesn’t outline clear boundaries on acceptable ways to
provide information about unapproved uses

or offer protection from prosecution. (
See “
Label Sales in Jeopardy
,” The RPM Report, December 2007.

Drug manufacturers now see an opening to revisit the issue in the aftermath of the Supreme
Court’s opinion in the Vermont data mining case
Sorrell vs. IMS Health
. In that case, the high
court struck down as unconstitutional Vermont’s attempts to place rest
rictions on the use of
physician prescribing data by pharmaceutical companies for marketing purposes. (
See “
Mining Case Struck Down by Supreme Court
,” T
he RPM Report, July 2011.


majority opinion

immediately prompted questions from the legal community about
whether it made vulnerable certain FDA regulations, includi
ng the agency’s ban on most off
label promotion by pharmaceutical companies. Now, the appeal of a conviction of an Orphan
Medical (now
Jazz Pharmaceuticals
) sales representative, Alfred Caronia, may provide an early
test of whether off
label restrictions c
an withstand First Amendment scrutiny.

, which is pending before the U.S. Court of Appeals for the Second Circuit, attorneys
for the former sales representative argue that FDA’s restrictions on off
label promotion are a
violation of the free spee
ch provisions of the Constitution. And they say that the restrictions
contain the same speaker

and content
based discrimination that was struck down by the
Supreme Court in

as unconstitutional.

Many legal experts agree. Richard Cooper, a former FD
A chief counsel and partner at
& Connolly
, told the Food & Drug Law Institute’s Advertising & Promotion Conference on
September 26 that like
, the off
label restrictions in

apply only to a certain class
of speakers (manufacturers of

regulated products) and certain content (promotion of
unapproved uses). As a result, Cooper says,

“puts FDA’s ban on off
label promotion in
some jeopardy.”

Industry has also jumped into the fray. A coalition of 11 drug manufacturers filed an

brief with the Second Circuit arguing that the court should overturn Caronia’s conviction,
because the FDA regulations on which it was based contain the same speaker

and content
restrictions that were struck down in
. And they argue tha
t existing FDA regulations lack
the “coherence and clarity” to provide manufacturers with the guidance they need on off

The government dismisses that argument, saying in briefs to the Second Circuit that

no bearing on
The off
label restrictions do not “tilt the playing field,” but rather ensure
that the public receive “reliable information” about drug and biologics. Furthermore, the
government says, FDA’s guidance document creates clearly defined safe harbors, and so lo
ng as
manufacturers stay within those established boundaries, there is no danger of prosecution.

But a First Amendment argument in

may be heard by sympathetic ears. It was the
Second Circuit, after all, that reversed a lower court decision in

and deemed Vermont’s
data mining restrictions to be a violation of the First Amendment

a decision the Supreme Court
upheld. If the same logic can be applied to the

case, major changes to off
promotion may be on the horizon.


A Rare

Label Prosecution

The ink was barely dry on
Sorrell vs. IMS Health

before legal pundits starting speculating on the
implications of the majority opinion on FDA’s regulation of the pharmaceutical industry.

Now that the Supreme Court had deemed unconsti
tutional restrictions on the use of physician
prescribing data, what might that mean for direct
consumer advertising? Or FDA’s Risk
Evaluation & Mitigation Strategies? Or the federal anti
kickback statute? Or off
promotion? Could the same logic th
at guided the Supreme Court’s decision in

other First Amendment challenges? (
See “
Interpreting a Surprisingly Broad Decision
,” The
RPM Report,

July 2011.)

Indeed, Supreme Court Justice Stephen Breyer suggested that very possibility in his dissenting
opinion in
: “The same First Amendment standards that apply to Vermont here would
apply to similar regulatory actions taken by other States o
r by the Federal Government acting, for
example, through Food and Drug Administration regulation.” The majority opinion “opens a
Pandora’s Box of First Amendment challenges to many ordinary regulatory practices that may
only incidentally affect a commercia
l message.”

An early test of that theory is playing out in the U.S. Court of Appeals for the Second Circuit.
The court is considering the appeal of sales representative Alfred Caronia’s conviction for
conspiracy to misbrand the narcolepsy drug

m oxybate). A federal court convicted
Caronia in 2008 after rejecting a motion to dismiss the case on First Amendment grounds. (

The Super FDA: State Att
orneys General Flex Their Muscles
,” The RPM Report, February

Caronia’s prosecution was based on a sting operation during which Steven Charo, a government
informant, met with Caronia and an Orphan medical expert, Peter Gleason, to talk about
hich was approved only for

associated with
. Charo asked a number of
questions about the off
label use for
excessive daytime sleepiness; at the time, the indication was
under review by FDA. The agency approved the excessive daytime sleepiness indication shortly
after the sting operation.

Caronia was convicted in federal court of conspiring to distribute

ithout adequate
directions of use

in essence, promoting the drug for the off
label indication of excessive
sleepiness. He was sentenced in 2008 to one
year probation, 100 hours of community service and
a $25 fine. According to “The Pink Sheet,” he is now t
rying to make a living as a carpenter. (
“Sales Rep’s Free Speech Challenge Of Off
Label Regs Boosted By Sorrell Ruling,” The Pink
Sheet,” September 5, 2011.


was the rare case in which prosecutors not only went after the drug marketer for off
label promotion, but also charged the individual sales representative with a crime. For industry,
the case was an ominous indication of where the government might be taking off
prosecutions. Indeed, in a later case, two sales managers for
Pfizer Inc.
’s valdecoxib (
were convicted for obstruction of justice in an off
label promotion investigation as part of a
breaking $2.3 billion settlement. (
See “Bextra Settlement Coming Soon: Industry Should
Brace For Impact,” The RPM Report, February

A New Off
Label Weapon?

After Caronia’s attorneys appealed his case to the Second Circuit, the court initially said it would
issue a decision without hearing oral arguments

an indication that it was prepared to uphold the
conviction. But then the co
urt reversed that decision, and scheduled oral arguments to further
examine both the constitutionality of FDA’s off
label restrictions, as well as questions about the
validity of the verdict sheet during the federal court trial.

Oral arguments, which were

heard on December 2, 2010, focused primarily on the
constitutionality question and appeared to play in Caronia’s favor. The appeals court judges
challenged the government on a number of points, including whether FDA is restricting speech
(the government s
ays no; the speech is merely evidence of intent to misbrand a drug), and
whether the agency could find less restrictive ways to achieve the same ends (such as putting
“timetables” on a manufacturer to seek approval).


was still pending at the Second

Circuit when the Supreme Court issued the

opinion in June 2011, striking down Vermont’s data
mining restrictions as unconstitutional. In
light of that decision, the Second Circuit asked the parties involved in the

case to submit
briefs on
the relevance of the Supreme Court’s opinion on

The appeals court request yielded

briefs from the usual suspects, like the
Legal Foundation
, which has been at the forefront of the off
label issue for years. But industry
also got
on board, with a brief from the
Medical Information Working Group
, a coalition of
11 drug manufacturers. (
See Exhibit 1.
) Both parties agree with attorneys for Caronia that

can be applied to FDA’s off
label promotion restrictions.

“Although they target a somewhat different subject matter, the FDA regulations at issue in this
case are not less speaker

and content
based than was the law at issue in
,” the Medical
Information Working Group’s brief states. “There is little quest
ion that the misbranding
provisions…impose substantial limitations on speech (i) by particular speakers (manufacturers)
and (ii) based on specific content (off
label uses of approved drugs and medical devices).”

The off
label restrictions restrict the spee
ch of manufacturers, while payors and other parties can
openly discuss unapproved uses, the coalition says. And the regulations are content
based in that
they “do not prohibit dissemination of truthful, non
misleading speech about on
label uses, but
do pro
hibit, in most circumstances, dissemination of information pertaining to off
label uses,
regardless of how medically accepted such uses are.”

“In sum, the FDA’s regulations censor manufacturers: A manufacturer that speaks about the
lawful off
label uses of

its products subjects itself to potential enforcement action unless FDA
and DOJ determine, in their sole discretion, that they will not treat the speech as evidence of an
‘intended use’ for the product.” This, MIWG says, creates a “chill on manufacturers’

which has serious potential consequences for physicians, patients, and the public health.”

The Government’s Response

The government doesn’t see it that way.

“does not affect the constitutionality of
Caronia’s conviction,” the government’s
brief to the Second Circuit states. The Supreme Court’s
decision to view the Vermont statute as a restriction on commercial speech (rather than
regulation of conduct) and apply “heightened judicial scrutiny” does not set new legal precedent,
the brief argu
es. “If the Court had actually meant to take such a drastic step, it surely would have
said so.”

But even if

did raise the judicial scrutiny for restrictions on commercial speech, it would
not affect
, the government’s brief continues. “Caro
nia was not convicted for conspiring
to promote off
label uses of
, but instead for conspiring to distribute

adequate directions for use, and both the Second Circuit and the Supreme Court “have long
employed a more relaxed standard of ju
dicial review when the government requires disclosure of
commercial information.”

The government also dismisses the argument that the restrictions are speaker
based. “To the
extent that the Act’s misbranding provisions are effectively confined to manufactu
rers and others
involved in drug distribution, that practical incidence reflects the realities of drug marketing, not
a preference for one speaker over another. By their very nature, regulations of commercial
speech ordinarily and unavoidably apply to pers
ons engaged in particular commercial activity
rather than to the world at large.”

Similarly, the restrictions are not content
based, the government’s brief continues. When the law
“requires a drug manufacturer to provide adequate directions for the intende
d uses of its drugs, it
does so not because of official hostility to the manufacturer’s message, but simply to ensure that
physicians and patients receive the information they need to use the drug safely and effectively.”

The FD&C Act’s misbranding provisi
ons “are not designed to favor one side of a public debate
over the other side, but instead to provide the public with reliable information about the
medicines they are using, in much the same fashion that securities laws provide the public with
reliable i
nformation about the investments that they are making.”

, this is not a case in which the government is animated by ‘fear that people
would make bad decisions if given truthful information,’” the brief states. Rather, off
promotion “in
volves representations of safety and efficacy that are scientifically unproven and
potentially false, and physicians and patients who rely on those representations may do so to the
detriment of the patients’ health and even their lives.

casts no do
ubt on provisions that
protect the public from these harms.”

Speech or Conduct?

There are some important distinctions between


that may yield a different
outcome in the Second Circuit. As the government points out in its brief, the Vermo
nt law was
designed to limit the promotion of brand
name drugs for approved uses.
, in contrast,
involves the promotion of drugs for unapproved uses.

That distinction,
Wiley Rein LLC

partner Bert Rein said at the FDLI conference, means that a
sal of

is by no means a sure thing. “

comes up in a context where the
pharmaceutical detailing is assumed to be truthful, non
misleading promotion,” namely, the on
label sale of drugs, Rein says. “In that framework, the court was very sensit
ive to the state trying
to tip the balance of what it otherwise would allow to be a lawful consumer decision.”

With off
label use as seen in
, the government’s rationale is somewhat different, he
continues. The government argues that the off

itself is not the crime, but the

of introducing a misbranded drug. The government, Rein says, is arguing: “We’re not
punishing the speech, but we don’t want you to sell these drugs for which you have not provided
an adequate evidence for safe
ty and effectiveness.”

And that may well be a deciding factor in how the Second Circuit views
. “It’s a real
conundrum,” Rein says. “If you treat it all as speech restriction, then suddenly it’s very
vulnerable. But if you start looking at, is the p
urpose here is to check the ideas or suppress an
activity which in the public health interest ought to be suppressed, you may come to a different

Cooper, the former FDA general counsel, agrees that the frame of reference matters, but thinks
the Co
urt will see it in free speech terms. “Perhaps the fundamental difference between the court
and the dissenters in

was on whether the Vermont statute should be viewed as a
restriction of speech, or merely as an incidental restriction in aid of gener
al economic
regulation,” he said. (
See “
A Case for Caronia

“Arguably, the same issue would apply to off
label promotion, and presumably, the same 6
t in the court would occur. FDA would argue that it is regulating conduct and regulating
shipment of interstate commerce, and not regulating speech.”

But, he says, the Supreme Court “didn’t accept that argument in
, and I think it’s doubtful
that t
he court would accept it in the context of off
label promotion.”

Incentivizing Supplemental NDAs

Cooper argues that the last defense that the government has in

is the incentive that the
label restrictions creates for companies to gain FDA appro
val of new indications. It’s a
justifiable concern: Without restrictions on off
label promotion, the government fears that
manufacturers would skip the supplemental approval process altogether

resulting in far less
information about the safety and efficacy

of drugs for patients and physicians.

But Cooper argues that the incentive simply doesn’t work. “The relatively small number of
supplements that are submitted for additional uses, compared to the very large number of off
label uses that occur, suggest tha
t the incentive isn’t particularly successful,” he says. “Given the
volume of information about off
label uses that is available to speakers other than manufacturers,
it is not surprising that the incentive is relatively weak.”

Besides, Cooper says, while
the Supreme Court recognized in
Thompson vs. Western States

importance of preserving the integrity of FDA’s new drug approval process, the government can
reach that goal with less restrictive steps then a ban on off
label promotion.

The Washington Leg
al Foundation, in an

brief to the Second Circuit, agrees. The
government’s interest in “providing incentives to submit approved drugs to the FDA for new
uses is a legitimate one. But, as in Western States, the means of accomplishing that goal

ting speech

is not narrowly tailored because that interest could be achieved by restricting
other conduct or far less speech than the current ban.”

The appeals court seemed to hear that message. During oral arguments, Justice Reena Raggi
pressed the govern
ment on that point, suggesting other ways that the off
label restrictions could
be more narrowly tailored, such as setting a timetable for approval of the supplemental
indication, or withdrawing the drug from the market if it is found to be unsafe. “The co
ncept of
precluding speech is one we look at with some concern,” Raggi said. “And so I’m not sure why
this can’t be much more narrowly tailored.”

In the case of
, there was no need for an incentive for Orphan Medical to file a
supplemental application, since

was already under review for the use of excessive
sleepiness. The Washington Legal Foundation makes this point in its

brief: “The FDA
ban on speech about uses that are

going through the approval process if obviously
overbroad and gratuitous, because there is no need to give the manufacturer an ‘incentive’ to do
what it is already doing.”

“Clarity and Coherence”

n the absence of a court ruling striking down FDA’s restrictions on off
label promotion as
unconstitutional, the pharmaceutical industry might be satisfied with more clearly defined rules
about marketing drugs for unapproved uses. Industry has long complai
ned that the current
environment for pharmaceutical marketing is fraught with ambiguity, and leaves manufacturers
without the necessary guidelines to market their products without fear of prosecution.

Indeed, some in industry wonder whether this is an are
a where regulators are deliberately vague,
counting on uncertainty to do what regulation cannot: stop companies from making truthful
statements about their own products.

A provision of the FDA Modernization Act of 1997 allowed manufacturers to disseminate
reviewed journal articles discussing off
label use of their medications, so long as the company
has plans to submit a supplemental application to FDA covering the use of the drug. But that
“safe harbor” expired on September 30, 2006, and while FDA iss
ued a
guidance document

on its
reprint policy in January 2009, companies have been left without statutory protection ever since.

Indeed, FDA guidance documents by de
finition “do not establish legally enforceable rights or
responsibilities” but instead “describe the Agency’s current thinking on a topic, and should be
viewed only as recommendations.” Those phrases, included in every FDA guidance document,
underscore the

fleeting protections that guidance documents afford manufacturers.

Revisiting WLF: Rules for Off
Label Promotion Could Change with the New Commissioner
The RPM Report, Novemb
er 2006

In its brief to the Second Circuit on
’s significance in the

case, the government
dismisses any concerns that FDA guidance documents are not binding on the agency and are not
embodied in formal rulemaking. “FDA and DOJ have

rought an enforcement action
against a manufacturer on the basis of conduct that conforms to the guidances,” the
government’s brief says. “The risk of liability for a manufacturer who engages in such conduct is

Still, MIWG, the industry coalition, ar
gues that while the government has carved out exceptions
where it will not pursue prosecution, “rather than creating any true ‘safe harbors,’ those asserted
‘exceptions’ to the general rule that manufacturers are prohibited from engaging in off
h are too narrow, too ambiguous, not rooted in and often inconsistent with the statutory
language of the FDCA, generally not the products of formal agency rulemaking, and in most
instance explicitly ‘non

For example, FDA’s guidance document on g
ood reprint practices allows that if a manufacturer
distributes a reprint of peer
reviewed journal article, the agency will not consider that action as
establishing intent to promote an unapproved use. Yet, the industry brief says, “if a scientist
for the manufacturer drafts and disseminates an entirely accurate summary of the
research on which that journal article was based, the manufacturer could be subject to

The result, as the Washington Legal Foundation argues in its

to the Second Circuit,
has been a contradictory off
label promotion policy. Physicians can prescribe medications for
unapproved uses for their patients

uses that are often paid for by the government through
Medicare. But they cannot discuss those uses with

other medical professionals (theoretically
more sophisticated than most patients) if they are on the payroll of the drug marketer

they are answering a direct question about that use.

“That regulatory regime

which allows doctors to recommend that pa
tients use

for off
label uses but prohibits manufacturers from encouraging those recommendations

survive First Amendment scrutiny.”

The Citizen Petition Route

Manufacturers say it’s that sort of ambiguity that makes any off
label promotion tre
Immediately after the

opinion, a group of seven manufacturers (
Allergan Inc.
Eli Lilly
& Co.
Johnson & Johnson
Novo Nordisk
Pfizer Inc.
, and
) filed a citizen
petition with FDA asking for clarification on communication
s about unapproved uses. (

FDA Pressed To Clarify Permissible Formulary, Clinical Guideline Communications
,” The
Pink Sheet,” July 6, 2011.

The citizen petition asked for clarification on four areas: details on the standards

for providing
medical and clinical information on investigational products (often called “scientific exchange”);
sharing information with formulary committees and payers; providing independent third
clinical practice guidelines; and responding to un
solicited requests for information.

The “confusion” among those in industry with FDA’s policies in those areas “results in
significant difficulties for companies in their day
day decision
making,” the citizen petition
says. “That lack of clarity places
manufacturers at risk of criminal or civil sanctions if they
cannot correctly guess where the government would draw a line….Industry should not have to
refer to the terms of DOJ settlements or informal statements of FDA officials to learn what is
of them.”

Whether industry will get greater clarity from FDA on off
label promotion is uncertain:
“Companies always do better with clarity,”
Pharmaceutical Research & Manufacturers of

General Counsel Diane Bieri said at the FDLI conference. “Whethe
r or not it’s possible
to get to the level of clarity that the companies are asking for, I’m not certain. But I think the
petition is a sincere attempt to try and get…a higher degree of clarity on some issues that have
troubled the industry for a number of


The Second Circuit may end the need for “clarity” from FDA on off
label promotion if it
reverses the

conviction. Until a decision comes down

perhaps as soon as this year

industry should play by the same rulebook. “As a practical matter, I
don’t think that

changed the US Attorney’s world

certainly without further clarification from the courts,” Bieri

John Kamp, a partner at Wiley Rein LLC, agrees. “This is an information policy debate and a
constitutional policy debate that is
fascinating and important, but the law didn’t change,” he told
the FDLI conference. The Department of Justice and the state AGs “are bringing those cases
under the same authority they brought before this case was decided. So don’t go home and say,
‘Oh, we
learned about the IMS case while we were at FDLI, and we don’t have to worry about
those rules anymore. Yes, you do.’”

The RPM Report

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